Pharmacology of Local Anesthetics and Specific Agents

Lecture given on 8/28/2025

are local anesthetics an acid or base, and why is this important?

basic compounds, they are poorly soluble and unstable on exposure to air

why is it valuable to know that local anesthetics are weakly basic?

informs you that they combine readily with acids to form local anesthetic salts which are more stable and quite soluble in water

what form of local anesthetics are used for injection?

acid salts (most commonly hydochloride salt), dissolved in sterile water or saline

in the local anesthetic solution that is used for injection, what are the molecules it exists as?

uncharged (base) molecules and positively charged cations

what does the relative proportion of each ionic form of molecules in a local anesthetic solution vary depending on?

the pH of the solution or surrounding tissue

in the presence of a high concentration of hydrogen ions (low pH), the equilibrium shifts to the ____, and most of the anesthetic solution exists in the _____ form

left, cationic

in the presence of a low concentration of hydrogen ions (high pH), the equilibrium shifts to the ________

free base form

the relative proportion of ionic forms depends on the presence of hydrogen ions and the ____ of the specific local anesthetic

pKa or dissociation constant

pKa

a measure of the affinity of a molecule for hydrogen ions

when the pH of the solution has the same value as the pKa of the local anesthetic…

exactly 50% of the drug exists in the RNH+ form and 50% in the RN form

what is the relationship between pKa of the local anesthetic and the percentage of base (RN) at pH 7.4 (pH of tissue)?

the lower the pKa, the higher the percentage of base at pH 7.4

what is the pKa, the percentage of base at a pH of 7.4, and approximate onset of action of benzocaine?

3.5, 100%, less than 1 minute

what is the pKa, the percentage of base at a pH of 7.4, and approximate onset of action of procaine?

9.3, 1%, 14-18 minutes

what is the relationship beween pKa and the approximate onset of action?

the lower the pKa, the lower the approximate onset of action is

when a local anesthetic is injected, where does it begin the process of dissociating/reaching equilibrium?

in the extracellular space

when the local anesthetic is injected into tissue, where do the lipophillic RN molecules diffuse?

intracellularly through the nerve sheath

once the RN molecule of the local anesthetic penetrates the nerve sheath and enters the axoplasm, what happens?

re-equilibration because the local anesthetic molecules cannot exist only in the RN form intracellularly

what happens intracellularly when the RN molecules re-equilibrate in the axoplasm?

the RHN+ ions enter the sodium channels, bind to the channel receptor site, and are responsible for the conduction blockade that results

when tissue is inflammed, which decreases the pH of the tissue to 6, will more or less local anesthetic molecules equilibrate to the base form, and will this allow for more or less to penetrate into the intracellular space?

less, less

which local anesthetics fall into the esters category?

butacaine, cocaine, benzocaine, hexilcaine, piperocaine, tetracaine, chloroprocaine, procaine, propoxicaine

which local anesthetics fall into the amides group?

articaine, bupivacaine, dibucaine, etidocaine, lidocaine, mepivacaine, prilocaine

which local anesthetics fall into the quinoline category?

centbucridine

t/f most local anesthetics produce vasodilation

true, this is why vasoconstrictors are often added to the carpule

which local anesthetic is the most potent vasodilator?

procaine

which local anesthetic is the only vasoconstrictor?

cocaine (after initial dilation)

what is the mechanism of cocaine that causes vasoconstriction?

inhibition of the uptake of catecholamines (especially norepinephrine) into tissue binding sites results in excess of free norepinephrine which produces an intense state of vasoconstriction

t/f local anesthetic drugs are absorbed well from the GI tract after being ingested orally

false

what percentage of the absorbed local anesthetic drug is metabolized on the first pass through the liver?

50-90%

how quickly is local anesthetic absorbed through tracheal mucosa?

almost as rapidly as IV administration

how quickly is local anesthetic absorbed through intact skin?

does not matter, there is no anesthetic action

what has been developed to provide surface anesthesia for intact skin?

eutectic mixture of local anesthetics (EMLA)

what is the rate of absorption after parenteral administration related to?

the vascularity of the injection site and the vasoactivity of the drug

IV administration

provides the most rapid elevation of blood levels, used in the primary management of ventricular dysrhythmias

what does the blood level of a drug after IV administration depend on?

rate of absorption into CVS, rate of distribution, elimination of the drug

t/f all local anesthetics cross the blood brain barrier and the placenta

true

what does drug toxicity depend on?

rate of absorption into the bloodstream at the site of injection

rate of removal from the blood through the process of tissue uptake and metabolism

what is the biotransformation that an ester local anesthetic will go through?

hydrolyzed in the plasma by the enzyme pseudocholinesterase

atypical pseudocholinesterase

causes an inability to hydrolyze ester local anesthetics, has an incidence rate of 1 out of every 2800 persons

what is the biotransformation that an amide local anesthetic will go through?

a very complex process that occurs primarily in the liver

amides are usually present as the parent compound in greater percentage than…

esters

slower than normal biotransformation rate leads to…

increased anesthetic blood levels and potentially increases toxicity

what are factors that may lead to a slower than normal biotransformation rate?

low hepatic blood flow (hypotension and congestive heart failure), or poor liver function (cirrhosis)

approximately how many half lives does it take to eliminate a drug from the system?

6

what are the primary excretion organ for both local anesthetics and its metabolites?

kidneys

what are the anticonvulsant properties of local anesthetics on the central nervous system?

it can terminate seizures at a dose of 2-3 mg/kg given at a rate of 40-50 mg/min

what is the preconvulsive phase of local anesthetics action on the central nervous system?

direct depressant action of the local anesthetics on the central nervous system, symptoms are slurred speech, shivering, muscular twitching, and tremor in muscle of face and distal extremities

inhibitory impulses are depressed

what is the convulsive phase of local anesthetics action on the central nervous system?

further elevation of the local anesthetic blood levels produces clinical signs and symptoms consistent with a generalized tonic-clonic convulsive episode

what is the final stage of local anesthetics action on the central nervous system?

both inhibitory and facilitory impulses are totally depressed, producing general CNS depression aka coma

what effect do local anesthetics have on the cardiovascular system?

decreases electrical excitability of the myocardium, decreases conduction rate, and decreases the force of contraction

certain local anesthetics such as bupivacaine (and to a lesser degree ropivacaine and etiodocaine) may precipitate potentially fatal _______

ventricular fibrilation

what are the pharmacological actions and parameter values of a non-overdose level of local anesthetic on the CVS?

enhanced sympathetic activity causing direct vasoconstriction

slight increase to no change in BP, increased CO and HR

what are the pharmacological actions and parameter values of levels below overdose of local anesthetic on the CVS?

direct relaxant action on the vascular smooth muscle

mild degree of hypotension

what are the pharmacological actions and parameter values of an overdose level of local anesthetic on the CVS?

decreased myocardial contractility, cardiac output, and peripheral resistance

profound hypotension

what are the pharmacological actions and parameter values of lethal levels of local anesthetic on the CVS?

cardiovascular collapse is noted, massive peripheral vasodilation and decreased myocardial contractility

sinus bradycardia

what effect do local anesthetics have on the respiratory system at non-overdose levels?

direct relaxant action on bronchial smooth muscle

what effect do local anesthetics have on the respiratory system at overdose levels?

may produce respiratory arrest as a result of generalized CNS depression

generally, how is respiratory function affected by local anesthetics?

unaffected until near-oversode levels are achieved

what happens when CNS depressants like opioids/antianxiety drugs/phenothiazines/barbiturates are administered in conjunction with local anesthetics?

there is a potentiation of te CNS depressant actions of local anesthetic

the conjoint use of local anesthetics and drugs that share a common metabolic pathway can produce…

adverse reactions, prolonged apnea may result from concomitant use of these drugs

drugs that induce the production of hepatic microsomal enzymes (like barbiturates) may alter…

the rate at which amide local anesthetics are metabolized

increased hepatic microsomal enzyme induction increases…

the rate of metabolism of the local anesthetic

what affects the duration of anesthesia from local anesthetics?

individual response to a drug, accuracy in drug deposition, status of tissues at the site of deposition, anatomical variation, type of injection administered

what distribution curve is expected in response to a drug?

bell shaped curve

what patients have a potentially increased risk associated with local anesthetics?

small children, elderly individuals, and medically compromised patients

when someone has a bisulfite allergy, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

local anesthetic containing a vasoconstrictor

absolute

local anesthetic that does not contain a vasoconstrictor

when someone has atypical plasma cholinesterase, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

esters

relative

amides

when someone has methemoglobinemia, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

prilocaine

relative

other amides

when someone has significant liver disfunction, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

amides

relative

amides or esters but judiciously

when someone has significant cardiovascular issuses, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

high concentrations of vasoconstrictors

relative

low concentrations of vasoconstrictors

when someone has clinical hyperthyroidism, what drugs should be avoided, what kind of contraindication is this, and what is an alternative drug?

vasoconstrictors

relative

low concentraion of vasoconstrictors

A category of drugs for use in pregnancy

adequate, well controlled studies in pregnant women have not shown an increased risk of fetal abnormalities

B category of drugs for use in pregnancy

animal studies have revealed no evidence of harm to the fetus; however there are no adequate and well controlled students in pregnant women OR animal studies have shown an adverse effect, but adequate and well controlled studies in pregant women have failed to demonstrate that risk

C category of drugs for use in pregnancy

animal studies have shown an adverse effect and there are no adequate and well controlled studies in pregnant women OR no animal studies have been conducted and there are no adequate and well controlled studies in pregnant women

D category of drugs for use in pregnancy

studies, adequate and well controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk

X category of drugs for use in pregnancy

studies, adequate and well controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. the use of the product is contraindicated in women who are or may become pregnant

benzocaine

ester type local aneshtetic for temporary relief of pain associated with toothache, minor sore throat pain, and canker sore

why is benzocaine not available in dental cartridges?

lack of efficacy, potential for allergenicity, advantages of newer aminoamides

lidocaine

dental uses: amide type injectable local anesthetic and topical local anesthetic

medical uses: local anesthetic and acute treatment of ventricular arrhythmias from myocardial infarction

allergies to amide local anesthetics like lidocaine, mepivaciane, articane, prilocaine, and bupivacaine is …

virtually nonexistent

what is the pregnancy classification, lactation recommendation, and maximum dosage of lidocaine?

B, safe, 7mg/kg (max 500mg)

what is the pulpal and soft tissue duration of analgesia of lidocaine 2%?

5-10 min

60-120 min

what is the pulpal and soft tissue duration of analgesia of lidocaine 2% with epi?

60 min

3-5 hrs

mepivacaine

dental uses: local infiltration anesthesia, injection near nerve trucks to produce nerve block

produces slight vasodilation

what is the pregnancy classification, lactation recommendation, and maximum dosage of mepivacaine?

C, safe, 6.6 mg/kg (max 400mg)

what is the pulpal and soft tissue duration of analgesia of mepivacaine 3%?

20-40 min

2-3 hrs

articaine

dental use: anesthesia agent for infiltration and nerve block anesthesia in clinical dentistry

degradation occurs in the plasma and liver

*methemoglobinemia is a potential complication

what is the pregancy classification and maximum dosage of articaine?

C, 7.0 mg/kg

what is the pulpal and soft tissue duration of analgesia of articaine 4% with epi 1:200,000?

45-60 min

2-5 hrs

what is the pulpal and soft tissue duration of analgesia of articaine 4% with epi 1:100,000?

60-75 min

3-6 hrs

bupivacaine

dental uses: local anesthesia

medical uses: local anesthesia

what are the indications for bupivacaine?

lengthy dental procedures and management of postoperative pain

what is the preganacy classification, lactation recommendation, and maximum dose for bupivacaine?

c, caution, 90mg

what is the pulpal and soft tissue duration of analgesia of bupivacaine (marcaine) with epi 1:200,000 ?

90-180 min

4-9 hrs

prilocaine

dental uses: local infiltration anesthesia, injection near nerve trunks to produce nerve block

where/how is prilocaine metabolized?

hydrolyzed in the liver to orthotoluidine and N-propylalanine

orthotoluidine can induce methemoglobinemia

what is the pregancy classification, lactation recommendation, and maximum dose for prilocaine?

B, caution, 8.0 mg/kg (max 600mg)

what patients is prilocaine contraindicated for?

idiopathic or congential methemoglobinemia, hemoglobinopathies (sickle cell), anemia, cardiac or respiratory failure evidence by hypoxia, patient’s receiving acetaminophen or phenacetin

what is the pulpal and soft tissue duration of analgesia of prilocaine 4% with epi 1:200,000?

60-90 min

3-8 hrs

what is the pulpal and soft tissue duration of analgesia of prilocaine 4%?

10 min for infiltration, 60 min for block

1.5-2 hrs for infiltration, 2-4 hrs for block

what are some factors to consider when selecting a local anesthetic?

procedure length time, post treatment pain comfort (minimizes pain meds that need to be prescribed after), possibility of self-mutilation during the postoperative period, hemostasis, medical status of the patient